Pyridinyl cyclohexanecarboxamide cooling compounds

ABSTRACT

A method of providing a cooling effect to a product includes the incorporation into the product of at least one compound of the formula I 
                         
in which m is a number between 0 and 2, X, Y and Z are selected independently from the group consisting of H, halogen, OH, Me, Et, MeO and EtO, and R 1 , R 2  and R 3  together comprise at least 6 carbons, selected such that
         (a) (i) R 1  is selected from the group consisting of H, Me, Et, isopropyl and C 4 -C 5  branched alkyl; and    (ii) R 2  and R 3  are independently selected from the group consisting of Me, Et, isopropyl and Ca-branched alkyl; or   (b) any two or all of R 1 , R 2  and R 3  together form a monocyclic, bicyclic or tricyclic radical having up to 10 carbons.       

     The compounds confer substantial cooling effects on compositions applied to the skin or taken orally, such as toothpastes, mouthwashes, foodstuffs, beverages, confectionery, tobacco products, skin creams and ointments.

The present application is a continuation of co-pending U.S. Ser. No.11/990,103, having a 371(c) date of Sep. 16, 2009, which is a 371 ofPCT/CH2006/000427, filed Aug. 14, 2006, which claims the benefit of thefiling date under 35 USC § 119(e) of U.S. Provisional Patent ApplicationNo. 60/708,153, filed on Aug. 15, 2005, which applications areincorporated herein by reference.

This invention relates to cooling compounds.

Cooling compounds, that is, chemical compounds that impart a coolingsensation to the skin or the mucous membranes of the body, are wellknown to the art and are widely used in a variety of products such asfoodstuffs, tobacco products, beverages, dentifrices, mouthwashes andtoiletries.

One class of cooling compounds that have enjoyed substantial successconsists of N-substituted p-menthane carboxamides. Examples of thesecompounds are described in, for example, British Patents GB 1,351,761-2and U.S. Pat. No. 4,150,052.

It has now been found that a particular selection of such compoundsexhibits a cooling effect that is both surprisingly strong andlong-lasting. A method is provided, therefore, of providing a coolingeffect to a product, comprising the incorporation into the product of atleast one compound of the formula I

in which m is a number between 0 and 2, X, Y and Z are selectedindependently from the group consisting of H, halogen, OH, Me, Et, MeOand EtO, and R¹, R² and R³ together comprise at least 6 carbons,selected such that

-   -   (a) (i) R¹ is selected from the group consisting of H, Me, Et,        isopropyl and C₄-C₅ branched alkyl; and    -    (ii) R² and R³ are independently selected from the group        consisting of Me. Et, isopropyl and Ca-branched alkyl; or    -   (b) any two or all of R¹, R² and R³ together form a monocyclic,        bicyclic or tricyclic radical having up to 10 carbons.

Me is defined as methyl, and Et is defined as ethyl.

Examples of cyclic radicals as described under (b) above include3-para-menthyl, bornyl and adamantyl.

The compounds of formula (I) may comprise one or more chiral centres andas such may exist as a mixture of stereoisomers, or they may be resolvedas isomerically pure forms. Resolving stereoisomers adds to thecomplexity of manufacture and purification of these compounds and so itis preferred to use the compounds as mixtures of their stereoisomerssimply for economic reasons. However, if it is desired to prepareindividual stereoisomers, this may be achieved according to methodsknown in the art, e.g. preparative HPLC and GC or by stereoselectivesyntheses.

In some embodiments, the compounds are those in which X, Y, Z are H, OH,Me or OMe. In certain embodiments, the compounds are those in which m is2; X, Y and Z are H or Me and R¹, R² and R³ are taken from Table 1.

TABLE 1 Exemplary R¹, R² and R³ groups. R¹ R² R³ H bornyl H 3-p-menthylH isopropyl isopropyl methyl isopropyl isopropyl ethyl ethyl ethyladamantyl

A particularly effective compound is that in which R¹ is H and R² and R³together form a 3-p-menthyl ring.

Examples of effective compounds are(1R,2S,5R)-2-isopropyl-5-methyl-N-(pyridinalkyl)cyclohexanecarboxamideand (2S,5R)-2-isopropyl-5-methyl-N-(pyridinalkyl)cyclohexanecarboxamide.Particular examples of these are(1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamideand(2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide.

Certain of the compounds are novel. A compound is therefore provided ofthe formula I as hereinabove described, in which m=2 and X, Y, Z, R¹,R², R³ have the meanings given hereinabove, with the proviso that whenR² and R³ form a para-menthyl ring, at least one of R¹, X, Y and Z is amoiety other than H.

A compound is also provided according to formula I as hereinabovedescribed, in which X, Y, Z, R¹ are H and R², R³ have the meanings givenhereinabove. In certain embodiments R¹ is hydrogen and R² and R³ areindependently selected from the group consisting of Me, Et and C₃-C₄branched alkyl; or R¹, R² and R³ together form a monocyclic, bicyclic ortricyclic radical having up to 10 carbons.

The compounds may be easily prepared and isolated by art-recognizedmethods.

They are distinguished from similar compounds of the prior art by theirsurprisingly high cooling effect (up to 100 times higher than that ofsimilar known compounds) and by the longevity of the cooling effect.These compounds also have a high solubility in oily solvents, such asmint oils, and acidic aqueous solutions, such as soft drinks. Thesefeatures expand the uses of cooling compounds to a larger variety ofproducts.

The compounds may be used in products that are applied to the mouth orthe skin to give a cooling sensation. By “applying” is meant any form ofbringing into contact, for example, oral ingestion or, in the case oftobacco products, inhalation. In the case of application to the skin, itmay be, for example, by including the compound in a cream or salve, orin a sprayable composition. There is also provided, therefore, a methodof providing a cooling effect to the mouth or skin by applying thereto aproduct comprising a compound as hereinabove described.

The range of products in which the compounds may be used is very wide,and it includes by way of example only, dentifrices such as toothpasteand toothgel, mouthwashes, foodstuffs, beverages, confectionery, tobaccoproducts, skin creams and ointments, both cosmetic and medicinal.

The compounds may be used alone or in combination with other coolingcompounds known in the art, e.g., menthol, menthone, isopulegol, N-ethylp-menthanecarboxamide (WS-3), N,2,3-trimethyl-2-isopropylbutanamide(WS-23), menthyl lactate (Frescolat™ ML), menthone glycerine acetal(Frescolat™ MGA), mono-menthyl succinate (Physcool™), mono-menthylglutarate, O-menthyl glycerine (CoolAct™ 10),menthyl-N,N-dimethylsuccinamate and 2-sec-butylcyclohexanone(Freskomenthe™).

Certain embodiments are now further described by means of the followingnon-limiting examples.

EXAMPLE 1 Preparation of N-(4-pyridinyl) p-menthanecarboxamide

To a flask are added 4.7 g (50 mmol) of pyridin-4-ylamine, 4.04 mL ofpyridine and 100 mL MtBE. To this mixture, 10 g of p-menthanecarboxylchloride are added dropwise over 5 minutes. The reaction mixture isstirred for 24 hours. To the reaction mixture, 50 mL of water are added.The mixture is separated. The organic layer is washed with 50 mL ofwater and 50 mL of brine. The organic layer is dried over MgSO₄. Thesolvent is evaporated in vacuo to afford the crude product, which isrecrystallized from hexanes to afford 6.2 g of the desired product withthe following spectroscopic properties:

MS: 260 ([M^(+·)]), 217, 149, 121, 95

¹H NMR (300 MHz; CDCl₃) δ: 8.49 (d, 2H), 7.77 (s, 1H), 7.52 (d, 2H),2.22 (td, 1H), 1.9 (broad d, 2H), 1.85-1.57 (m, 3H), 1.44-1.22 (m, 2H),1.16-0.99 (m, 2H), 0.94 (d, 3H), 0.91 (d, 3H), 0.81 (d, 3H)

¹³C NMR (75 MHz; CDCl₃) δ: 175.4, 150.5, 145.0, 113.4, 50.7, 44.3,39.25, 34.3, 32.1, 28.7, 23.7, 22.1, 21.2, 16.1

EXAMPLE 2 Preparation of N-(2-pyridin-2-ylethyl) p-menthanecarboxamide[(1R,2S,5R)-2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexanecarboxamide]

A preparation similar to that described in example 1 gives the desiredproduct with the following spectroscopic properties:

MS: 288 ([M^(+·)]), 273, 245, 149, 121, 95

¹H NMR (300 MHz; DMSO) δ: 8.53 (d, 1H), 7.62 (td, 1H), 7.16 (m, 2H),6.43 (s, 1H), 3.67 (nontuplet, 2H), 3.00 (t, 2H), 1.95 (td, 1H),1.84-1.53 (m, 4H), 1.47 (broad t, 1H), 1.4-1.1 (m, 2H), 0.87 (d, 3H),0.84 (d, 3H), 0.66 (d, 3H)

¹³C NMR (75 MHz; DMSO) δ: 175.8, 159.7, 148.9, 136.7, 123.6, 121.55,49.8, 44.3, 39.4, 38.35, 36.9, 34.6, 32.3, 28.55, 23.9, 22.3, 21.3,15.95

EXAMPLE 3 Preparation of2-isopropyl-2,3-dimethyl-N-(2-(pyridin-2-yl)ethyl)butanamide

A preparation similar to that described in example 1, using2-isopropyl-2,3-dimethylbutanoyl chloride, gives the desired productwith the following spectroscopic properties:

MS: 262 ([M+]), 220, 205, 149, 121, 106, 93

¹H NMR (300 MHz; CDCl3) 8.53 (d, 1H), 7.63 (t, 1H), 7.16 (m, 2H), 6.69(s, 1H), 3.67 (dd, 2H), 2.99 (t, 2H), 1.96 (m, 2H), 0.96 (s, 3H), 0.85(d, 6H), 0.79 (d, 6H)

13C (75 MHz; CDCL3) 175.6, 160.0, 149.1, 136.6, 123.4, 121.5, 51.4,38.4, 36.9, 32.6, 18.1, 17.4, 14.1

EXAMPLE 4 Assessment of Cooling Effect

A small group of panelists is asked to taste various aqueous solutionsof cooling compounds and indicate which solutions had a coolingintensity similar or slightly higher than that of a solution of mentholat 2 ppm. The same panel is asked to taste these solutions at the chosenconcentrations and to record the cooling intensity at regular timeintervals until no cooling could be sensed in the mouth. The results areshown in Table 2.

TABLE 2 Experiments on cooling intensity and longevity. ChemicalConcentration Longevity 1-Menthol 2.0 ppm 35 minutes N-ethylp-menthanecarboxamide (WS-3) 1.5 ppm 57 minutes Formula I, m = 0, X = Y= Z = R1 = H, 0.5 ppm 50 minutes R2 + R3 = p-menthyl (compound ofExample 1) Formula I, m = 2, X = Y = Z = R1 = H, 0.02 ppm 60 minutesR2 + R3 = p-menthyl (compound of example 2) Formula I, m = 2, X = Y = Z= H, 0.4 ppm R1 = methyl, R2 = R3 = isopropyl (compound of example 3)

From Table 2, it can be seen that the compounds of Formula I are up to100 times stronger and last longer than menthol, the reference coolingcompound. Compounds of Formula I are also much stronger than WS-3, thebest cooling compound of the prior art.

In a second experiment, the same panel is asked to taste varioussolutions of compounds having various concentrations and to indicatewhich of these solutions had a cooling intensity similar to or slightlyhigher than that of a solution of menthol at 2 ppm. This is the“isointensive concentration”. The results are shown in Table 3.

TABLE 3 Intensity of compounds where R² + R³ = p-menthane and R¹ = X = Y= Z = H Value of m Position of main Isointensive (Chain length) moietyon ring concentration 0 2 or 6  0.2 ppm 0 3 or 5  0.4 ppm 0 * 4 *  0.5ppm 1 2 or 6  0.67 ppm 1 3 or 5  0.25 ppm 1 4  0.2 ppm 2 ** 2 or 6 ** 0.02 ppm 2 3 or 5 0.004 ppm 2 4  0.05 ppm * compound of Example 1 **compound of Example 2

From Table 2 and 3, it can be seen that compounds of Formula I withvarious chain lengths and substitution patterns all have lower usagelevels than the reference cooling chemicals, menthol and WS-3.

EXAMPLE 5 Application in Mouthwash

Alcohol 95% 177 mL Sorbitol 70% 250 g Compound of example 1 as a 50 mL1% solution in alcohol Peppermint oil, Terpeneless 0.300 g Methylsalicylate 0.640 g Eucalyptol 0.922 g Thymol 0.639 g Benzoic acid 1.500g Pluronic ™ F127 nonionic surfactant 5.000 g Sodium Saccharin 0.600 gSodium Citrate 0.300 g Citric Acid 0.100 g Water q.s. 1 liter

All the ingredients are mixed. 30 mL of obtained solution is put in themouth, swished around, gargled and spit out. An icy-cool sensation isfelt in every area of the mouth as well as lips.

EXAMPLE 6 Application in Toothpaste

Opaque toothgel 97.000 g Compound of example 2 as a 2% 2.500 g solutionin propylene glycol Peppermint oil, Terpeneless 0.500 g

The chemicals are mixed in the toothgel, a piece of toothgel is put on atoothbrush and a panelist's teeth are brushed. The mouth is rinsed withwater and the water is spit out. An intense cooling sensation is felt bythe panelist in all areas of the mouth.

EXAMPLE 7 Application in Beverages

1.5 mg of the compound of example 2 is dissolved in a 355 mL (12 fl oz.)can of clear lemon/lime soda. A panelist experiences an agreeabledelayed cooling sensation in the mouth with no throat burning. Nounpleasant after-taste is observed.

Although the invention has been described in detail through the abovedetailed description and the preceding examples, these examples are forthe purpose of illustration only and it is understood that variationsand modifications can be made by one skilled in the art withoutdeparting from the spirit and the scope of the invention. It should beunderstood that the embodiments described above are not only in thealternative, but can be combined.

The invention claimed is:
 1. A method of providing a cooling effect to aproduct, comprising the incorporation into the product of at least onecompound of the formula I

wherein a) m is a number between 0 and 2, X, Y and Z are selectedindependently from the group consisting of H, halogen, OH, Me, Et, MeOand EtO, R¹ is hydrogen and R² and R³ are independently selected fromthe group consisting of Me, Et, and C₃-C₄ branched alkyl; or b) m is 2,X is Me, Y and Z are H, R¹ is H, and R² and R³ together form3-p-menthyl.
 2. The method according to claim 1, in case a), wherein X,Y, and Z are independently selected from H, OH, Me and OMe.
 3. Themethod according to claim 1, in case a), wherein m is 2; X, Y, and Z areindependently selected from H and Me, R¹ is H and R² and R³ areisopropyl.
 4. The method according to claim 1, wherein the compound offormula I is used in combination with at least one other coolingcompound comprising menthol, menthone, isopulegol, N-ethylp-menthanecarboxamide, N,2,3-trimethyl-2-isopropylbutanamide, menthyllactate, menthone glycerine acetal, mono-menthyl succinate, mono-menthylglutarate, O-menthyl glycerine, menthyl-N,N-dimethylsuccinamate, or2-sec-butylcyclohexanone.
 5. A product adapted to be applied to the skinor taken orally, comprising at least one compound of the formula I

wherein a) m is a number between 0 and 2, X, Y and Z are selectedindependently from the group consisting of H, halogen, OH, Me, Et, MeOand EtO, R¹ is hydrogen and R² and R³ are independently selected fromthe group consisting of Me, Et, and C₃-C₄ branched alkyl; or b) m is 2,X is Me, Y and Z are H, R¹ is H, and R² and R³ together form3-p-menthyl.
 6. The product according to claim 5, in case a), wherein X,Y, and Z are independently selected from H, OH, Me and OMe.
 7. Theproduct according to claim 5, in case a), wherein m is 2; X, Y, and Zare independently selected from H and Me, R¹ is H and R² and R³ areisopropyl.
 8. The product according to claim 5, wherein the productfurther comprises at least one other cooling compound selected from thegroup consisting of menthol, menthone, isopulegol, N-ethylp-menthanecarboxamide, N,2,3-trimethyl-2-isopropylbutanamide, menthyllactate, menthone glycerine acetal, mono-menthyl succinate, mono-menthylglutarate, 0-menthyl glycerine, menthyl-N,N-dimethylsuccinamate, and2-sec-butylcyclohexanone.
 9. The method according to claim 1, wherein inthe at least one compound of formula I, m is 2, X is Me, Y and Z are H,R¹ is H, and R² and R³ together form 3-p-menthyl.
 10. The productaccording to claim 5, wherein in the at least one compound of formula I,m is 2, X is Me, Y and Z are H, R¹ is H, and R² and R³ together form3-p-menthyl.